Reaction #2339

Reaction equation

4-[4-(4-pyridyl)piperazin-1-yl]phenol

sodium hydride

ethyl-4-bromo-3-methylbutyrate

→

ethyl 3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate

Solvents

DMF

Conditions

Workup

1. 1
   workup.STIRRINGthe mixture stirred for 16 hours
2. 2
   OtherSolvent was evaporated
3. 3
   Otherthe residue partitioned between water and dichloromethane
4. 4
   OtherInsoluble material was removed by centrifugation
5. 5
   FiltrationThe organic layer was filtered through phase
6. 6
   Otherseparating paper (Whatman IPS)
7. 7
   Otherthe residue was purified by flash chromatography on silica gel by elution with methanol/dichloromethane/concentrated ammonia (50/950/5)

Procedure

To a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.02 g) in dry DMF (10 ml) was added sodium hydride (60% dispersion in mineral oil, 0.16 g) and the mixture stirred for 1 hour at room temperature. To the resulting solution was added ethyl-4-bromo-3-methylbutyrate and the mixture stirred for 16 hours. Solvent was evaporated and the residue partitioned between water and dichloromethane. Insoluble material was removed by centrifugation. The organic layer was filtered through phase separating paper (Whatman IPS) and the residue was purified by flash chromatography on silica gel by elution with methanol/dichloromethane/concentrated ammonia (50/950/5) to give ethyl 3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (0.27 g) which was hydrolysed in methanol (3 ml) and aqueous sodium hydroxide (1N, 2 ml) for 2 hours at room temperature. The solution was evaporated and the residue purified by reverse phase h.p.l.c (water/acetonitrile/0.1% TFA gradient) to give a glass which crystallised on trituration with ether to give the title compound (0.08 g): m.p. 169°-171° C.; NMR(d6DMSO) δ 13.45(1H,broad), 2.07(1H,broad) 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m), 2.37(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+ ; calculated for C22 H25N3O4F3. 0.5 H2O: C, 55.2; H, 5.6; N, 8.9. Found: C, 55.3; H, 5.6; N, 8.7%.

Source